The present invention relates to new medicament compositions based on anticholinergic compounds, which have a long-lasting effect, and xcex2-mimetics, which have a long-lasting effect, processes for their production and their use in the therapy of respiratory ailments.
It is known from the prior art that xcex2-mimetics and anticholinergics can successfully be used as bronchospasmolytics for the treatment of obstructive respiratory ailments, such as, e.g., asthma, Substances with xcex2-sympatho-mimetic effectiveness, such as, e.g., the active substance formnoterol, also known from the prior art, can, however, be associated with undesirable side-effects when administered to humans.
Generally, the central effects manifest as unease, excitation, sleeplessness, fear, shaking fingers, outbreaks of sweating and headaches. Here, inhalative application does not exclude these side-effects although they are generally less severe than with peroral or parenteral application.
The side-effects of the xcex2-sympatho-mimetics used as asthma agents are primarily associated with a more or less pronounced xcex21-stimulating effect on the heart. It generates tachycardia, palpitation, angina pectoris-like complaints and arrhythmia [P. T. Ammon (Ed.), Medicament Side-effects and Interactions, Wissenschaftliche Verlagsgesellschaft, Stuttgart 1986, S. 584].
Surprisingly, it has now been found that the above-mentioned side-effects can be substantially reduced by a combination of a xcex2-sympatho-mimetic, which has a long-lasting effect, with an anticholinergic, which has a long-lasting effect.
In addition, it was also very surprisingly discovered that the bronchospasmolytic effects of the anticholinergic, which has a long-lasting effect, and the xcex2-mimetic, which has a long-lasting effect, increase in a superadditive manner.
Hence with the combination of active ingredients according to the invention, a substantial increase in effectiveness can be expectedxe2x80x94in comparison to the individual substances and combinations known from the prior artxe2x80x94in the case of both COPD and asthma.
The following active ingredients can preferably be used as xcex2-mimetics, which have a long-lasting effect, in the active ingredients combination according to the invention: bambuterol, bitolterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenalin, ibuterol, pirbuterol, procaterol, reproterol, salmeterol, sulfonterol, terbutalin, tolubuterol, 4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulfonyl}ethyl]-amino}ethyl]-2(3H)-benzothiazolone, 1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-3-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol, 5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one, 1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert-butylamino)ethanol or 1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert-butylamino)ethanol, optionally in the form of their racemates, their enantiomers, their diastereomers, and mixtures thereof, and optionally their pharmacologically-compatible acid addition salts.
The following are preferably used as xcex2-mimetics, which have a long-lasting effect, in the active ingredients combination according to the invention: formoterol, salmeterol, 4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulfonyl}ethyl]-amino}ethyl]-2(3H)-benzothiazolone, 1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol or 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]2-methyl-2-butylamino}ethanol, optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally their pharmacologically-compatible acid addition salts.
Especially preferably, the following are used as xcex2-mimetics in the medicament compositions according to the invention: formoterol or salmeterol, optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally their pharmacologically-compatible acid addition salts.
As stated above, the xcex2-mimetics which have a long-lasting effect can be converted and used in the form of their physiologically and pharmacologically-compatible salts. The following can be considered, by way of example, to represent the acid addition salts: hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanosulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid or maleic acid. Furthermore, mixtures of the aforementioned acids can be used.
From the viewpoint of the superadditive bronchospasmolytic effect, the fumarate of formoterol (abbreviated to formoterol FU) is especially preferred as a xcex2-mimetic which has a long-lasting effect. Here, the active substance formoterol can be used as an enantiomer or diastereomer mixture or in the form of the individual enantiomers/diastereomers. With the same preferred significance, according to the invention, salmeterol can also be used as a xcex2-mimetic which has a long-lasting effect, optionally in the form of its racemates, enantiomers, of which the (R) enantiomer is most especially preferred, and optionally its pharmacologically-acceptable addition salts.
As anticholinergics which have a long-lasting effect, basically those which are already known from the prior art, such as glycopyrronium bromide and esters of bi- and tricyclic amino alcohols, are suitable, such as are known from European disclosure document 0 418 716 and International Patent Application WO 92/16528, and to the full contents of which reference is hereby made.
Within the framework of the invention, glycopyrroniumbromide can especially be considered as an anticholinergic which has a long-lasting effect, and compounds of formula (I) 
can be considered as esters of bi- and tricyclic amino alcohols wherein
A denotes a group of general formula (II) 
xe2x80x83in which
Q denotes one of the double-bonded groups xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, 
xe2x80x94CHxe2x95x90CHxe2x80x94, or;
R denotes an optionally halogen- or hydroxy-substituted C1-C4 alkyl group,
Rxe2x80x2 denotes a C1-C4 alkyl group and R and Rxe2x80x2 can also combine to form a
C4-C6 alkylene group, and
an equivalent of an anion X is counters the positive charge of the N atom,
Z denotes one of the groups 
xe2x80x83wherein
Y represents a single bond, an O or S atom or one of the groups xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94OCH2xe2x80x94 or xe2x80x94SCH2xe2x80x94;
R1 denotes hydrogen, OH, C1-C4 alkoxy or C1-C4 alkyl, which can optionally be substituted by hydroxy;
R2 denotes a thienyl, phenyl, furyl, cyclopentyl or cyclohexyl group, wherein these groups can also be substituted by methyl, and thienyl and phenyl can also be substituted by fluorine or chlorine,
R3 denotes hydrogen or a thienyl or phenyl group, which can optionally be substituted by halogen or C1-C4 alkyl,
optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof.
Within the framework of the invention, glycopyrroniumbromide can especially preferably be considered as an anticholinergic which has a long-lasting effect, and compounds of formula (I) can be considered as esters of bi- and tricyclic amino alcohols, wherein
A denotes a group of general formula (II) 
xe2x80x83in which
Q denotes one of the double-bonded groups xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94 or 
R denotes a methyl, ethyl or propyl group, optionally substituted by fluorine or hydroxy,
Rxe2x80x2 denotes methyl, ethyl or propyl, preferably methyl, and an equivalent of an anion X selected from the group comprising chloride, bromide and methanesulphonate, preferably bromide, counters the positive charge of the N atom,
Z denotes one of the groups 
xe2x80x83wherein
Y represents a single bond or an O atom;
R1 denotes hydrogen, OH, methoxy, ethoxy, propoxy, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, or hydroxypropyl;
R2 denotes a thienyl, phenyl, or cyclohexyl group, wherein these groups can also be substituted by methyl, and thienyl and phenyl can also be substituted by fluorine or chlorine,
R3 denotes hydrogen, or a thienyl or phenyl group which can optionally be substituted by fluorine, chlorine or methyl,
optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof.
According to the invention, medicament compositions in which compounds of formula (I) are used as anticholinergics which have a long-lasting effect are of special significance, wherein
A denotes a group of general formula (II) 
xe2x80x83in which
Q denotes one of the double-bonded groups xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94 or 
R denotes methyl or ethyl;
Rxe2x80x2 denotes methyl; and
an equivalent of the anion X=bromide is positioned opposite the positive charge of the N atom,
Z denotes one of the groups 
xe2x80x83wherein
Y denotes an O atom;
R1 denotes hydrogen, OH or hydroxymethyl;
R2 denotes a thienyl, phenyl or cyclohexyl group; and
R3 denotes hydrogen, thienyl or phenyl group,
optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof.
Of the compounds named above, within the framework of the present invention those of the 3-xcex1 position are especially preferred.
The described anticholinergic active substances can optionally be used in the form of their pure enantiomers, mixtures thereof or their racemates.
It is especially preferred that tiotropium salt, especially tiotropium bromide [(1xcex1,2xcex2,4xcex2,5xcex1,7xcex2)-7-[(hydroxy-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4]nonane bromide monohydrate (abbreviated to tiotropium BR)] is used as an anticholinergic.
As alkyl groups (even insofar as they are components of other groups), unless otherwise defined, branched and unbranched alkyl groups with 1 to 4 carbon atoms are considered. By way of example, methyl, ethyl, propyl or butyl are named. Insofar as not otherwise named, all of the possible isomeric forms of the hereinbefore-named designations propyl and butyl are included. For example, the designation propyl includes the two isomeric groups n-propyl and isopropyl, the designation butyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Optionally, common abbreviations are used to designate the hereinbefore-named alkyl groups, such as Me for methyl, Et for ethyl, etc.
As alkoxy groups (even insofar as they are components of other groups), unless otherwise defined, branched and unbranched alkyl groups, bridged via an oxygen atom and with 1 to 4 carbon atoms, are considered. The following are named by way of example: methoxy, ethoxy, propoxy (=propyloxy) or butoxy (=butyloxy). Here too, insofar as not otherwise named, all of the possible isomeric forms of the hereinbefore-named designations propoxy and butoxy are included.
Branched and unbranched alkylene bridges with 4 to 6 carbon atoms are considered as alkylene groups. The following are named by way of example: butylene, pentylene, and hexylene. Insofar as not otherwise named, all of the possible isomeric forms of the hereinbefore-named designations butylene, pentylene, hexylene are included. For example, the designation butylene includes the isomers n-butylene, 1-methylpropylene, 2-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene, etc.
Generally, fluorine, chlorine, bromine, or iodine are designated as halogen.
Insofar as not otherwise mentioned, anion X is generally designated as fluorine, chlorine, bromine, iodine, methanesulphonate, fumarate, or citrate.
The active substance compositions according to the invention are preferably administered in the form of a dosing aerosol, however, any other form or parenteral or oral application is possible. Here, the application of dosing aerosols embodies the preferred application form, especially in the therapy of obstructive lung diseases or for the treatment of asthma.
Apart from applications in aerosols which operate via propellant gases, the active substance combinations according to the invention can also be administered by means of so-called atomisers, via which solutions of pharmacologically-active substances can be sprayed under high pressure so that a mist of inhalable particles results. The advantage of these atomisers is that the use of propellant gases can be completely dispensed with.
The medicaments intended for inhalation are usually dissolved in an aqueous or ethanolic solution, wherein solvent mixtures of ethanol or water are also suitable, depending on the solution characteristics of the active substances.
Such atomisers are described, for example, in PCT Patent Application No. W091/14468 and International Patent Application PCT/EP96/04351, reference here being made to the contents thereof. With the atomisers described here, which are also known under the designation Respimat(copyright), defined volumes of solutions containing active substances are sprayed at high pressure through small jets so that inhalable aerosols result with a preferred particle size of between 1 and 10, preferably between 2 and 5 micrometres.
Amongst others, mixtures which, e.g., contain ethanol as a solvent are suitable for use as solvents for medicament preparation.
Apart from water, other components of the solvent are optionally other co-solvents and the medicament preparation can also contain flavorings and other pharmacological adjuvants. Examples of co-solvents are those which contain hydroxyl groups or other polar groups such as alcoholsxe2x80x94especially isopropyl alcohol, glycolsxe2x80x94especially propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol, polyoxyethylene alcohols and esters of polyoxyethylene fatty acids. Co-solvents are suited to increasing the solubility of adjuvants and, optionally, the active substance. Other pharmacological adjuvants can be added, such as, e.g., preservatives, especially benzalkonium chloride. The preferred quantity of preservatives, especially benzalkonium chloride, is between 8 and 12 mg/100 ml solution.
Complex formers can be added to the active substance combination to avoid spray anomalies. Suitable complex formers are those which are pharmacologically-acceptable, especially those which are already permitted under drug licensing laws. EDTA, nitrilotriacetic acid, citric acid and ascorbic acid, and also their salts, are especially suitable. The disodium salt of ethylenediamtetraacetic acid is especially suitable.
The proportion of dissolved active substance composition in the finished medicament preparation is between 0.001 and 5%, preferably between 0.005 and 3%, and especially 0.01 to 2%. The maximum concentration of medicament is dependent on solubility in solvent and the necessary dosage for attaining the desired therapeutic effect.